Involvement of the Na+/Ca2+ Exchanger in Ouabain-Induced Inotropy and Arrhythmogenesis in Guinea-Pig Myocardium as Revealed by SEA0400

Tanaka, Hikaru; Shimada, Hideaki; Namekata, Iyuki; Kawanishi, Toru; Iida-Tanaka, Naoko; Shigenobu, Koki

doi:10.1254/jphs.fp0060911

Cited by 28 publications

(32 citation statements)

References 24 publications

(8 reference statements)

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“…This was in contrast with the effects of KB-R7943, a compound that has been widely used as an NCX inhibitor; KB-R7943 inhibited all of the above mentioned currents with equal potency (8). Thus, SEA0400 was established as the first specific pharmacological tool to study the role of NCX and was shown to be useful in studies on myocardial excitation-contraction mechanisms, regulation by autonomic transmitters, and ischemia-reperfusion injury (5,10,11). In the present study, we examined the effects of SEA0400 and ryanodine on the spontaneous and ouabain-induced electrical activity of the guinea-pig pulmonary vein myocardium to clarify the role of NCX in automaticity.…”

Section: +mentioning

confidence: 99%

Involvement of the Na+/Ca2+ Exchanger in the Automaticity of Guinea-Pig Pulmonary Vein Myocardium as Revealed by SEA0400

et al. 2009

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Abstract. We examined the involvement of the Na + /Ca 2+ exchanger in the automaticity of the pulmonary vein myocardium with a specific inhibitor, SEA0400. Action potentials were recorded from the myocardial layer of isolated guinea-pig pulmonary vein preparations, and Ca 2+transients were recorded from the cardiomyocytes. Spontaneous electrical activity was observed in 17.7% of the preparations, which was inhibited by either SEA0400 or ryanodine. In quiescent preparations, ouabain induced electrical activity and spontaneous Ca 2+ transients, which were inhibited by SEA0400, as well as ryanodine. These results provide pharmacological evidence that the Na + /Ca 2+ exchanger underlies the automaticity of the pulmonary vein myocardium.Keywords: pulmonary vein myocardium, NaPulmonary veins are considered to be involved in the initiation and maintenance of atrial fibrillation, one of the most frequent arrhythmias in clinical practice (1). Pulmonary veins contain a myocardial layer, whose electrical activity is considered to underlie their arrhythmogenic activity (2). The pulmonary vein myocardium has different electrophysiological properties from those of the working myocardium, including lower density of I K1 and a less negative resting membrane potential (3). The precise mechanisms of the pulmonary vein electrical activity as well as its pharmacological properties are now receiving attention as the basis to develop an effective therapeutic strategy against atrial fibrillation.The Na + /Ca 2+ exchanger (NCX) is involved in the physiological and pathophysiological regulation of Ca 2+ concentration in the myocardium. It functions both in the forward (Ca 2+ extrusion) and reverse (Ca 2+ influx) modes, and its functional role may vary with the region and the condition of the myocardium (4, 5). The forward mode NCX activity (inward current) is the major pathway for Ca 2+ extrusion from the cytoplasm and is also considered to be involved in the normal pacemaking of the rabbit sinoatrial node (6). It was postulated that the Ca 2+ released from the sarcoplasmic reticulum (SR) during the diastolic period is pumped out of the cell through the forward mode NCX, which generates an inward current that contributes to the diastolic depolarization of the pacemaker. Although it is possible that such a mechanism is involved in the automaticity of other myocardial regions including the pulmonary vein myocardium, pharmacological evidence is limited because of the lack of an NCX inhibitor with sufficient specificity. SEA0400 {2-[4-[(2,5-difluorophenyl) methoxy] phenoxy]-5-ethoxyaniline} is a potent and selective inhibitor of NCX in cultured neurons, astrocytes, microglia, dog sarcolemmal vesicles, and cultured rat myocytes with negligible affinities towards other transporters, ion channels, and receptors (7). We have previously shown that SEA0400 is a specific inhibitor of NCX in the myocardium (8, 9). SEA0400 (1 μM), which inhibited the NCX current by more than 80%, had no effect on the Na + current, L-type Ca 2+ current, delayed recti...

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Section: +mentioning

confidence: 99%

Involvement of the Na+/Ca2+ Exchanger in the Automaticity of Guinea-Pig Pulmonary Vein Myocardium as Revealed by SEA0400

et al. 2009

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“…The microscope was IX-70 (Olympus, Tokyo) and the objective was UApocromat 40x / 340 water immersion (Olympus). The cells were excited at 360 nm from a Xenon lamp and the emission bands, 395 to 415 nm and 470 to 490 nm, were separated (W-VIEW system; Hamamatsu Photonics, Hamamatsu), detected by a high-speed cooled CCD camera (C6790, Hamamatsu Photonics), and ratioed after correction of background fluorescence (Aquacosmos software, Hamamatsu Photonics) as in our previous studies (11,12).…”

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confidence: 99%

Involvement of Intracellular Ca2+ in the Regulatory Volume Decrease After Hyposmotic Swelling in MDCK Cells

et al. 2007

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Abstract. We examined the source of Ca 2+ involved in the volume regulation of Madin-Darby canine kidney (MDCK) cells with confocal microscopy and fluoroprobes. Hyposmosis induced a transient increase in cell volume, as well as cytoplasmic Ca 2+, which peaked at 3 to 5 min and gradually decreased to reach the initial value within about 30 min. This late decrease in cell volume, as well as the transient rise in cytoplasmic Ca 2+ , was reduced in Ca 2+-free solution and was abolished by pretreatment with thapsigargin. In conclusion, Ca 2+ released from the intracellular store contributes to the regulatory volume decrease following hyposmotic swelling in MDCK cells.

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“…Therefore, the most important requirement for a NCX inhibitorbeyond potent blocking of NCX -is a minimal influence on the I CaL current. In previous studies of our laboratory (10,28,55,83,84), we reported that ORM-10103 effectively (Figure 7.) and selectively inhibits NCX in dog ventricular myocytes without influencing the I CaL current (figure not shown). Furthermore it was effective against triggered arrhythmias, namely it clearly decreased the amplitude of pharmacologically induced EAD and reduced the DAD incidence.…”

Section: Orm-10103mentioning

confidence: 64%

“…The antiarrhythmic effect of selective NCX inhibition is controversial in the literature (43). NCX inhibitors have shown antiarrhythmic effects in hearth rhythm disturbances evoked by ischemia/reperfusion injury in vivo (44), in Langendorff perfused hearts (45)(46)(47)(48)(49)(50)(51), and in pharmacologically simulated ischemia/reperfusion models (52)(53)(54)(55)(56). The SEA0400 decreased the incidence (56), and reduced the development of EADs (57), it failed to suppress the aconitine induced arrhythmias (58).…”

Section: Transmural Heterogeneity In the Ventricular Myocardiummentioning

confidence: 99%

“…Previously, the most successfully used NCX inhibitors like KB-R7943 and SEA0400 considerably improved our knowledge about the role of NCX regarding the electromechanical coupling and arrhythmogenesis (55,(79)(80)(81)(82)(83), but these inhibitors were not appropriately selective i.e. certain amount of I CaL and I K currents contaminated the results making the data interpretation difficult.…”

Section: Orm-10103mentioning

confidence: 99%

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Characterization of different aspects of selective NCX inhibition in the heart

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Involvement of the Na+/Ca2+ Exchanger in Ouabain-Induced Inotropy and Arrhythmogenesis in Guinea-Pig Myocardium as Revealed by SEA0400

Cited by 28 publications

References 24 publications

Involvement of the Na+/Ca2+ Exchanger in the Automaticity of Guinea-Pig Pulmonary Vein Myocardium as Revealed by SEA0400

Involvement of the Na+/Ca2+ Exchanger in the Automaticity of Guinea-Pig Pulmonary Vein Myocardium as Revealed by SEA0400

Involvement of Intracellular Ca2+ in the Regulatory Volume Decrease After Hyposmotic Swelling in MDCK Cells

Characterization of different aspects of selective NCX inhibition in the heart

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